Abstract:Mutations in ATP13A2 (PARK9), encoding a lysosomal P-type ATPase, are associated with both Kufor-Rakeb syndrome (KRS) and neuronal ceroid lipofuscinosis (NCL). KRS has recently been classified as a rare genetic form of Parkinson's disease (PD), whereas NCL is a lysosomal storage disorder. Although the transport activity of ATP13A2 has not been defined, in vitro studies show that its loss compromises lysosomal function, which in turn is thought to cause neuronal degeneration. To understand the role of ATP13A2 d… Show more
“…2013) and recently in Atp13a2‐deficient (CLN12) mice (Schultheis et al. 2013). α ‐Synuclein is known to modulate synaptic pathology in mice, at least in part through interactions with another synaptic protein, CSP‐ α (Chandra et al.…”
AimsSynapses represent a major pathological target across a broad range of neurodegenerative conditions. Recent studies addressing molecular mechanisms regulating synaptic vulnerability and degeneration have relied heavily on invertebrate and mouse models. Whether similar molecular neuropathological changes underpin synaptic breakdown in large animal models and in human patients with neurodegenerative disease remains unclear. We therefore investigated whether molecular regulators of synaptic pathophysiology, previously identified in Drosophila and mouse models, are similarly present and modified in the brain of sheep with CLN5 Batten disease.MethodsGross neuropathological analysis of CLN5 Batten disease sheep and controls was used alongside postmortem MRI imaging to identify affected brain regions. Synaptosome preparations were then generated and quantitative fluorescent Western blotting used to determine and compare levels of synaptic proteins.ResultsThe cortex was particularly affected by regional neurodegeneration and synaptic loss in CLN5 sheep, whilst the cerebellum was relatively spared. Quantitative assessment of the protein content of synaptosome preparations revealed significant changes in levels of seven out of eight synaptic neurodegeneration proteins investigated in the motor cortex, but not cerebellum, of CLN5 sheep (α‐synuclein, CSP‐α, neurofascin, ROCK2, calretinin, SIRT2, and UBR4).ConclusionsSynaptic pathology is a robust correlate of region‐specific neurodegeneration in the brain of CLN5 sheep, driven by molecular pathways similar to those reported in Drosophila and rodent models. Thus, large animal models, such as sheep, represent ideal translational systems to develop and test therapeutics aimed at delaying or halting synaptic pathology for a range of human neurodegenerative conditions.
“…2013) and recently in Atp13a2‐deficient (CLN12) mice (Schultheis et al. 2013). α ‐Synuclein is known to modulate synaptic pathology in mice, at least in part through interactions with another synaptic protein, CSP‐ α (Chandra et al.…”
AimsSynapses represent a major pathological target across a broad range of neurodegenerative conditions. Recent studies addressing molecular mechanisms regulating synaptic vulnerability and degeneration have relied heavily on invertebrate and mouse models. Whether similar molecular neuropathological changes underpin synaptic breakdown in large animal models and in human patients with neurodegenerative disease remains unclear. We therefore investigated whether molecular regulators of synaptic pathophysiology, previously identified in Drosophila and mouse models, are similarly present and modified in the brain of sheep with CLN5 Batten disease.MethodsGross neuropathological analysis of CLN5 Batten disease sheep and controls was used alongside postmortem MRI imaging to identify affected brain regions. Synaptosome preparations were then generated and quantitative fluorescent Western blotting used to determine and compare levels of synaptic proteins.ResultsThe cortex was particularly affected by regional neurodegeneration and synaptic loss in CLN5 sheep, whilst the cerebellum was relatively spared. Quantitative assessment of the protein content of synaptosome preparations revealed significant changes in levels of seven out of eight synaptic neurodegeneration proteins investigated in the motor cortex, but not cerebellum, of CLN5 sheep (α‐synuclein, CSP‐α, neurofascin, ROCK2, calretinin, SIRT2, and UBR4).ConclusionsSynaptic pathology is a robust correlate of region‐specific neurodegeneration in the brain of CLN5 sheep, driven by molecular pathways similar to those reported in Drosophila and rodent models. Thus, large animal models, such as sheep, represent ideal translational systems to develop and test therapeutics aimed at delaying or halting synaptic pathology for a range of human neurodegenerative conditions.
“…In addition, PARK9 expression levels were increased in postmortem brains from sporadic PD patients (Ramirez et al, 2006;Ramonet et al, 2012). Studies in cultured neurons also demonstrated that transiently expressed wild-type PARK9 localized to acidic vesicles (Ramirez et al, 2006;Tan et al, 2011;Ramonet et al, 2012). We and others have shown that depletion of PARK9 causes lysosomal dysfunction, accumulation of ␣-syn (Dehay et al, 2012;Usenovic et al, 2012a), and increased sensitivity to zinc .…”
Section: Introductionmentioning
confidence: 90%
“…Initial studies revealed that overexpression of PARK9 reduced the toxicity of ␣-synuclein (␣-syn) in yeast cells and rat primary dopaminergic neurons (Gitler et al, 2009). In addition, PARK9 expression levels were increased in postmortem brains from sporadic PD patients (Ramirez et al, 2006;Ramonet et al, 2012). Studies in cultured neurons also demonstrated that transiently expressed wild-type PARK9 localized to acidic vesicles (Ramirez et al, 2006;Tan et al, 2011;Ramonet et al, 2012).…”
Section: Introductionmentioning
confidence: 94%
“…Loss-of-function mutations in ATP13A2/PARK9 cause KuforRakeb syndrome (KRS), a rare autosomal recessive disorder characterized by early onset parkinsonism and other neurological symptoms, such as dementia and pyramidal signs (Najim al-Din et al, 1994;Ramirez et al, 2006). PARK9 belongs to P-type ATPase super family to which no specific substrates have been assigned (Axelsen and Palmgren, 1998).…”
Section: Introductionmentioning
confidence: 99%
“…PARK9 belongs to P-type ATPase super family to which no specific substrates have been assigned (Axelsen and Palmgren, 1998). PARK9 is expressed predominantly in CNS, especially in dopaminergic neurons of substantia nigra (Ramirez et al, 2006). Initial studies revealed that overexpression of PARK9 reduced the toxicity of ␣-synuclein (␣-syn) in yeast cells and rat primary dopaminergic neurons (Gitler et al, 2009).…”
Kufor-Rakeb syndrome (KRS) is caused by loss-of-function mutations in ATP13A2 (PARK9) and characterized by juvenile-onset parkinsonism, pyramidal signs, and cognitive decline. Previous studies suggested that PARK9 deficiency causes lysosomal dysfunction and ␣-synuclein (␣-syn) accumulation, whereas PARK9 overexpression suppresses toxicity of ␣-syn. However, the precise mechanism of PARK9 effect on lysosomes and ␣-syn has been unknown. Here, we found that overexpressed PARK9 localized to multivesicular bodies (MVBs) in the human H4 cell line. The results from patient fibroblasts showed that loss of PARK9 function leads to decreased number of the intraluminal vesicles in MVBs and diminished release of exosomes into culture media. By contrast, overexpression of PARK9 results in increased release of exosomes in H4 cells and mouse primary cortical neurons. Moreover, loss of PARK9 function resulted in decreased secretion of ␣-syn into extracellular space, whereas overexpressed PARK9 promotes secretion of ␣-syn, at least in part via exosomes. Finally, we found that PARK9 regulates exosome biogenesis through functional interaction with the endosomal sorting complex required for transport machinery. Together, these data suggest the involvement of PARK9 in the biogenesis of exosomes and ␣-syn secretion and raise a possibility that disruption of these pathways in patients with KRS contributes to the disease pathogenesis.
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